`
`CHEMISTRY
`of
`ORGANIC
`COMPOUNDS
`
`CARL R. NOLLER
`Professor of Chemistry, Stanford University
`
`W. B. SAUNDERS COMPANY
`Philadelphia and London
`
`1965
`
`Page 1 of 15
`
`SENJU EXHIBIT 2104
`LUPIN v. SENJU
`IPR2015-01097
`
`
`
`Chemistry of Organic Compounds
`
`© 1965 by W. B. Saunders Company. Copyright 1951 and 1957 by W. B. Saunders Company.
`Copyright under the International Copyright Union. All rights reserved. This book is protected
`by copyright. No part of it may be duplicated or reproduced in any manner without written
`permission from the publisher. Made in the United States of America. Press of W. B. Saunders
`Company. Library of Congress catalog card number 65-10290.
`
`Page 2 of 15
`
`
`
`CHAPTER TWENTY-FOUR
`
`AROMATIC AMINES
`· AND PHOSPHINES
`
`Compounds classed as aromatic amines have an amino group or an alkyl- or aryl(cid:173)
`substituted amino group attached directly to an aromatic nucleus. Usually they are made
`by a procedure different from those for aliphatic amines and undergo additional reactions.
`Aromatic phosphines resemble the amines only in structure. Their methods of preparation
`and reactions are entirely different.
`
`AMINES
`
`Nomenclature
`Aromatic amines may be primary, secondary, or tertiary, and in the secondary or
`tertiary amines, the seconcJ- orr third hydrocarbon group may be alkyl or aryl. Usually the
`primary amines are named as amino derivatives of the aromatic hydrocarbon or as aryl
`derivatives of ammonia, but some are known best by common names such as aniline
`or toluidine.
`
`NH2
`
`0
`
`Aniline
`(aminoben;;;ene)
`
`CHa
`ONH2
`
`a-Toluidine
`( o-aminotoluene)
`
`NHz
`
`ONH2
`m-Phenylenediamine
`(m-diamirwbenzene)
`
`Secondary and tertiary amines are named as derivatives of the primary amine, or as deriv(cid:173)
`atives of ammonia.
`
`N(CHs)2 0
`
`N,N-Dimethylaniline
`( dimethylani/£ne)
`
`o -NH -D
`
`Diphenylamine
`
`Preparation
`1. By Reduction of More Highly Oxidized Nitrogen Compounds. Aromatic nitro
`compounds yield a series of reduction products, the final product being the primary amine
`(Fig. 23-/, p. 519). Therefore primary aromatic amines may be prepared from nitro com(cid:173)
`pounds or from the less highly oxidized nitroso, hydroxylamine, azoxy, azo, and hydrazo
`compounds, by reduction with alkaline hydrosulfite or with sodium and ethanoL
`2. By Ammonolysis of Halogen Compounds. Halogen attached to an aromatic
`nucleus usually is very stable to hydrolysis or ammonolysis, and rather drastic conditions
`are required to bring about reaction, which may occur with rearrangement (p. 495). If,
`however, electron-attracting groups are present in the ortho and para positions, the halogen
`
`523
`
`Page 3 of 15
`
`
`
`524
`
`is more easily displaced. Thus 2,4,6-trinitrochlorobenzene (picryl chloride) reacts readily with
`ammonia to yield 2,4,6-trinitroaniline (picramide) by an S;V:4 ,2 mechanism (p. 496):
`
`Cl
`02NOl';Oz
`
`NOz
`2, 4,6-Trinitrochlorobenzene
`( puryl chloride)
`
`NH,
`Ozl';~l ~,N02
`-~
`IJ
`~
`NOz
`2, 4 ,6· Trini troaniline
`( picrarmde)
`
`+ NH4Cl
`
`Physical Properties
`
`The physical properties of the aromatic amines are about what would be expected ..
`Just as benzene (b.p. 80o) boils at a higher temperature than n-hexane (b.p. 69°),
`aniline (b.p. 184o) has a higher boiling point than n-hexylamine (b.p. 130°).
`greater difference in the boiling points of the second pair may be ascribed to the fact that
`aniline has a higher dipole moment (p.
`1.6) than n-hexylamine (p. = 1.3).
`aniline (b.p. 195°) boils at a higher temperature than aniline, but N,N-dimethylaniline
`(b.p. 193°) boils at a lower temperature than methylaniline despite the increase in the
`number of electrons because proton bonding is not possible for dimethylaniline.
`Aniline is considerably more soluble in water (3.6 g. per 100 g. of water) than n-hexyl(cid:173)
`amine (0.4 g. per 100 g. of water). Water dissolves in aniline to the extent of about 5 per ·
`cent. Aniline is miscible with benzene but not with n-hexane.
`As is true for all of the disubstituted benzenes, the para-substituted anilines, being the
`most symmetric, have the highest melting point. Thus p-toluidine is a solid at room tem(cid:173)
`perature whereas both the ortho and meta isomers are liquids.
`
`Physiological Properties
`The aromatic amines, like the aromatic hydrocarbons and their halogen and nitro
`derivatives, are highly toxic. The liquids are absorbed readily through the skin, and low
`concentrations of the vapors produce symptoms of toxicity when inhaled for prolonged peri(cid:173)
`ods. Aniline vapors may produce symptoms of poisoning after several hours of exposure to
`concentrations as low as 7 parts per million. Aniline affects both the blood and the nerv~
`ous system. Hemoglobin of the blood is converted into methemoglobin with reduction of
`the oxygen-carrying capacity of the blood and resultant cyanosis. A direct depressant action
`is exerted on heart muscle. Continued exposure leads to mental disturbances. Aromatic
`amines appear to be responsible also for bladder irritation and the formation of tumors in
`workers engaged in the manufacture of dye intermediates.
`The chloro and nitro nuclear-substituted amines, the N-alkylated and acylated amines,
`and the diamines all are highly toxic. The N-phenylamines are considerably less toxic than
`the N-alkyl derivatives. The phenolic hydroxyl group also decreases the toxicity somewhat.
`Toxicity is greatly reduced by the presence of free carboxylic or sulfonic acid groups in the
`ring.
`
`Reactions of the Nucleus
`1. Hydrogen Exchange. Electrophilic substitution of deuterium for hydrogen of ben(cid:173)
`zene takes place only with strong acids under anhydrous conditions (p. 469). The amino
`group is so strongly activating, however, that exchange with hydrogen in the ortho and para
`positions takes place readily in aqueous solutions, although less readily than with the amino
`hydrogen. As would be expected, these exchange reactions are catalyzed by acids.
`
`Page 4 of 15
`
`
`
`CHAPTER 24.
`
`AROMATIC AMINES AND PHOSPHINES
`
`525
`
`cS
`
`NDz
`
`YD
`#
`
`D
`
`i5"
`
`D
`'
`
`ND.,
`
`DVD
`
`I#
`D
`
`b
`2. Oxidation. Aliphatic amines are fairly stable to oxidation, but many aromatic
`amines oxidize readily. Unless carefully purified, they soon darken on standing in air.
`Stronger oxidizing agents produce highly colored products. Even the simplest aromatic
`amine, aniline, can give rise to numerous and frequently complex oxidation products. It is
`not surprising that, depending on the oxidizing agent used, azobenzene, azoxybenzene,
`phenylhydroxylamine, nitrosobenzene, and nitrobenzene have been isolated (p. 519), since
`aniline is a reduction product of these compounds. In addition to the amino group, however,
`the hydrogen atoms of the benzene ring that are ortho and para to the amino group can be
`oxidized to hydroxyl groups because the amino group increases the electron density at the
`ortho and para positions. Thus when sodium hypochlorite solution is added to aniline,
`p-aminophenol is formed along with azobenzene and other products.
`
`NHz 0 +NaOCI
`
`NHo
`
`o·+NaCl
`
`OH
`
`These hydroxy amines are oxidized very readily to quinones (p. 566), which undergo
`further oxidation and condensation reactions. For example, the violet color produced when
`aniline is mixed with a solution of bleaching powder is due to a serie~ of reactions that form
`a blue compound known as indoaniline.
`
`NHz
`
`Q
`
`OH
`
`NCI ¢ C,H,;H,
`
`0
`Quinone
`chloroimine
`
`HO-oN=O=NH
`
`Indoaniline
`
`Some of the more complicated reactions are considered in the discussion of quinones
`(p. 567) and of the Aniline Blacks (p. 765 ).
`Amine salts are much less readily oxidized than the free amines because the positive
`charge makes the group electron-attracting rather than electron-donating. Similarly, electro(cid:173)
`negative substituents such as the nitro group decrease the electron density of the ring and
`greatly reduce the ease of oxidation.
`3. Halogenation. Because of the strong activating effect of the amino group, no
`catalyst is required in the halogenation of the nucleus. Furthermore, halogenation takes
`place in aqueous solution and is so rapid that the only product readily isolated is 2,4,6-tri(cid:173)
`chloro- or 2,4,6-tribromoaniline. The three halogen atoms in the ortho and para positions
`reduce the basicity of the amino group; and the salt does not fo~m in aqueous solution. ·
`
`Page 5 of 15
`
`
`
`526
`
`CHEMISTRY OF ORGANIC COMPOUNDS
`
`-->
`
`.
`
`Nih
`I /
`BrOBr
`+ 3 HBr
`Br
`2,4,6-Tribromo(cid:173)
`aniline
`
`Actually trichloroaniline or tribromoaniline is formed even when chlorine or bromine
`is added to an aqueous solution of an aniline salt. This behavior seems anomalous at first,
`since salt formation should lead to deactivation and meta orientation. The experimental re(cid:173)
`sults can be explained by the presence of free amine in equilibrium with the salt in aqueous
`solution. This view is confirmed by the fact that aniline dissolved in concentrated sulfuric
`acid is not chlorinated or brominated at room temperature. At higher temperatures the
`meta substitution product is formed.
`
`+
`
`NH3-S04H 0
`
`+Cb-->
`
`Aniline acid
`sulfate
`
`m-Chloroaniline
`acid sulfate
`
`Even the less reactive iodine substitutes aniline directly, the hydrogen iodide combin(cid:173)
`ing with unreacted aniline.
`
`NH2
`
`-->0
`
`I
`p-lodo(cid:173)
`aniline
`
`+
`
`Aniline hydroiodide
`(phenylammonium iodide)
`
`If the activating effect of the amino group is reduced by conversion to the acetamino group,
`monochloro or mono bromo derivatives can be obtained.
`
`NHCOCH3
`
`0~ --v
`
`Br
`p-Bromoacetanilide
`
`+ HBr
`
`Acetanilide
`
`Usually monohalogenated anilines are prepared by reduction of the halogenated nitro
`compounds.
`4. Nitration. Because of the ease of oxidation of free aniline (p. 525), only the salt
`can be nitrated efficiently, and nitration is carried out in concentrated sulfuric acid solu(cid:173)
`tion. Hence the chief product is m-nitroaniline.
`
`NH2 ONOz
`
`m-Nitroaniline
`
`Some o- and p-nitroaniline also are formed, probably by nitration of the small amount of
`free amine in equilibrium with its salt, since the amount of meta increases with the concen(cid:173)
`tration of the sulfuric acid ( cf. p. 527). The three nitroanilines differ in basicity (p. 528)
`and can be separated by fractional precipitation from their salts with alkali. The order of
`precipitation is ortho, then para, then meta. m-Nitroaniline usually is made by the partial
`reduction of m-dinitrobenzene (p. 517).
`
`Page 6 of 15
`
`
`
`CHAPTER 24.
`
`AROMATIC AMINES AND PHOSPHINES
`
`527
`If salt formation is prevented by the conversion of the basic amino group to the neutral
`acetamido group, nitration in acetic acid takes place almost exclusively in the para position.
`If the nitration is carried out in acetic anhydride, the ortho isomer is the chief product.
`
`HNO, in
`
`NHCOCH3 0
`
`Acetanilide
`
`NHCOCH3 0 NOz
`acetic anhydride ON02
`
`p-Nitroacetanilide
`
`HN03 in
`
`NHCOCH,
`
`o-Nitroacetanilide
`
`Saponification of the nitroacetanilides with sodium hydroxide solution gives the nitro(cid:173)
`anilines. p-Nitroaniline is an intermediate for the manufacture of Para Red (p. 744).
`5. Sulfonation. Sulfonation of aniline at room temperature with fuming sulfuric acid
`gives a mixture of o-, m-, and p-aminobenzenesulfonic acids. Since the effect of the +NH3
`group should be comparable to that of the +NRg group, it should lead to pure meta substi(cid:173)
`tution. Hence, as in nitration (p. 526), the ortho and para isomers probably arise from the
`sulfonation of the small amount of free amine in equilibrium with the salt. When aniline
`is heated with concentrated sulfuric acid for several hours at 180° (baking process), the sole
`product is the para isomer, sulfanilic acid. There is some evidence that here the initial
`product is the sulfamic acid, which should be ortho,para-directing.
`
`+
`NHs-sO,H
`
`0
`
`cr03H
`
`#
`Phenylsul-
`famic acid
`
`NHS03H
`
`0
`
`S03H
`
`H20
`
`02
`
`or better
`
`#
`S03H
`Sulfanilic acid
`
`03
`
`+
`
`#
`so3-
`
`.N,N-Dimethylaniline, however, behaves in the same way as aniline, and since it cannot
`form a sulfamic acid, para substitution is assumed to result from sulfonation of the free
`amine at both low and high temperatures.
`Although the formulas· for the sulfonated amines frequently are written as amino(cid:173)
`sulfonic acids, they actually are inner salts or dipolar ions ( cf. p. 441 ). Thus sulfanilic acid
`decomposes at 280-300° without melting, whereas aniline is a liquid, benzenesulfonic acid
`is a low melting solid, and both can be distilled. Whereas the amino carboxylic acids are
`more soluble in either strong base or strong acid than in water, sulfanilic acid is more
`soluble only in strong bases because the sulfonic acid group is as strong as any of the min(cid:173)
`eral acids in aqueous solution.
`The common names foro-, m-, and p-aminobenzenesulfonic acids are orthanilic, metanilic,
`and sulfamlic acids respectively. Metanilic acid is prepared by the reduction of m-nitroben(cid:173)
`zenesulfonic acid. Orthanilic acid is not readily available but can be obtained by removal
`of the bromine atom in 2-amino-5-bromobenzenesulfonic acid by reduction, or by reduc(cid:173)
`tion of o-nitrobenzenesulfonic acid made from o-nitrophenyl disulfide (p. 496) by oxidation.
`
`Reactions of the Amino Group
`1. Basicity. When an amino group is attached to an aromatic nucleus, the unshared
`pair of t:lectrons on nitrogen interacts with the '11' orbital system of the nucleus (p. 4 7 4) and
`makes the unshared pair less available for bonding with other groups. Moreover the elec(cid:173)
`tronegativity of the phenyl group is greater than that of an alkyl group because the greater s
`
`Page 7 of 15
`
`
`
`528
`
`CHEMISTRY OF ORGANIC COMPOUNDS
`
`character of the aryl sp 2 orbital pulls the electrons closer to the nucleus. Hence the basicity
`of aromatic amines is less than that of aliphatic amines, afthough it is still greater than that
`of amides. Thus the acidity constants (PKa's) of methylamine, aniline, and acetamide are
`10.6, 4.6, and -1.5 respectively. The introduction of a second aromatic nucleus on the
`nitrogen atom decreases the basicity still further, the pKa for diphenylamine being 0.9. On
`the other hand the introduction of alkyl groups increases the basicity, the pKa's for N-meth(cid:173)
`ylaniline and N,N-dimethylaniline being 4.8 and 5.1 respectively.
`The effects of substituents in the aromatic nucleus depend both on their inductive and
`resonance effects. The inductive effects depend on the distance separating the groups con(cid:173)
`cerned, and hence the order of effectiveness when in the various positions is o > m
`p.
`Resonance effects, however, are transmitted through conjugated systems and therefore are
`effective in the ortho and para positions but not in the meta positions.
`
`Resonance strong
`and induction strong
`
`Resonance weak
`and induction fair
`
`/:r;<"-.
`0~ ~0
`Resonance strong
`and induction weak
`
`For the nitro group the inductive and resonance effects are in the same direction. The pKa's
`foro-, m-, and p-nitroaniline are 0.3, 2.4, and 1.1 respectively. Although the inductive effect
`in the para position is less than that in the meta position, p-nitroaniline is a weaker base
`than m-nitroaniline because the resonance effect is added to the inductive effect. a-Nitro(cid:173)
`aniline is the weakest base because the resonance effect is operative and the inductive effect
`is at a maximum.
`2. Alkylation and Arylation.
`amines react with alkyl halides to
`ammoni urn salts.
`
`Like the aliphatic amines, the primary aromatic
`give secondary and tertiary amines and quaternary
`
`CsHsNHz + RX
`
`lC6 H 5NH2R)X- NaOH CsHsNHR + NaX + H20
`N-Aikylaniline
`
`CsH5NRz + NaX + H 20
`NNDi-
`alkylaniline
`
`CsHsNRz + RX --> [CsHsNR3]X(cid:173)
`Phen yltrialkyl(cid:173)
`ammonium halide
`
`Simple aryl halides react with difficulty. Although diphenylamine is a minor coproduct of
`the commercial production of aniline from chlorobenzene (p. 533), it is made best by heat(cid:173)
`ing aniline with aniline hydrochloride.
`
`C6HsNH 2 + fC 6H5NHa]CI- ~ (CGl-Is)2NH + Nff4Cl
`Diphenylamine
`
`Reaction of the lithium salt of a diarylamine with an aryl iodide in the presence of catalytic
`amounts of cuprous iodide yields the triarylamine. The lithium salt is prepared from the
`amine and phenyllithium.
`
`Page 8 of 15
`
`
`
`CHAPTER 24. - AROMATIC AMINES AND PHOSPHINES
`
`529
`
`3. Acylation. Acid anhydrides and acyl halides convert primary and secondary
`amines into the amides.
`
`CeH5NH2 + (CHaCO)zO --'> CsH5NHCOCH3 + CH3COOH
`Acetanilide
`+
`2 CsHsNHCH3 + CHsCOCl --'> CsH5N(CH3)COCH3 + [CeHsNH2CH3)CI-
`N-Methylacetanilide
`N-Methylani!ine
`N·Methylaniline
`hydrochloride
`
`Acylation can be brought about also by heating the amine salts of carboxylic acids (p. 186).
`
`CH3 0 +CH3COOH
`
`NHz
`p-1bluidine
`
`CHa
`
`0,~ ""
`
`+ H20
`NHCOCH3
`p-Acetotoluidide
`
`Reaction of aniline with phosgene gives phenylcarbamyl chloride. When it is heated,
`hydrogen chloride is lost and phenyl isocyanate is produced.
`
`NHz 0
`
`NHCOC! 0
`
`N=C=O 0
`
`Phenyl isocyanate
`
`+HCI
`
`Phenyl isocyanate is useful for the identification of alkyl halides. The latter can be
`converted to Grignard reagents, which add to phenyl isocyanate. Hydrolysis of the addi(cid:173)
`tion product gives a solid anilide.
`
`?MgX
`CsHsN=C=O + RMgX - -? CsHsN=CR
`
`~Q_, LcsHsN=CR J
`When phenyl isocyanate is used for the preparation of derivatives of alcohols and amines
`(p. 339), all moisture musfbe excluded. Otherwise the phenylcarbamic acid that is formed
`loses carbon dioxide, and the resulting aniline reacts with more phenyl isocyanate to give
`insoluble diphenylurea.
`
`?Hl
`
`1-
`
`CsHsN=C=O
`
`CsHsNHCONHCsHs
`
`Diphenylurea is one of the substances in coconut milk that stimulates the growth of plant
`cells. Various 1-aryl-1,3-dialkylureas and alkyl N-arylcarbamates are made commercially
`from aryl isocyanates for use as selective herbicides. An 80:20 mixture of 2,4- and
`2,6-tolylene diisocyanate (so-called toluene diisocyanate) made from the mixed diamino(cid:173)
`toluenes is of commercial importance for the manufacture of urethan plastics (p. 819).
`Production of isocyanates in 1962 was almost 94 million pounds.
`4. Reaction with Nitrous Acid. The behavior of aromatic amines toward nitrous
`acid, like that of the aliphatic amines, depends on whether the amine is primary, second(cid:173)
`ary, or tertiary. The reactions of primary and tertiary aromatic amines, however, differ
`from those of primary and tertiary aliphatic amines (p. 261 ).
`(a) PRIMARY AMINES. At temperatures below 0° in strongly acid solution, nitrous acid
`reacts with the primary aromatic amine salts to give water-soluble compounds known as
`diazonium salts.
`
`Page 9 of 15
`
`
`
`530
`
`CHEMISTRY OF ORGANIC COMPOUNDS
`
`Aniline
`hydrochloride
`
`Benzenediazon~
`ium chloride
`The properties and uses of these important compounds are described in Chapter 25.
`(b) SECONDARY AMINES. Secondary aromatic amines behave like secondary aliphatic
`amines and yield N-nitroso derivatives.
`
`CsH5NHCH3 + HONO
`N~methyl-
`aniline
`
`CGH5~CH3 + HzO
`NO
`N-Nitroso-N(cid:173)
`methylaniline
`
`(c) TERTIARY AMINES. Tertiary aromatic amines having an unsubstituted para position
`yield p-nitroso derivatives.
`
`N(CH3)2 0
`
`+HONO
`
`N(CH3)2 0 NO
`
`+ HzO
`
`N,N~Dimethyl
`p-Nitroso-,\~N-di
`aniline
`methylaniline
`This reaction takes place because of the strong activating effect of the dimethylamino
`group. Although most of the dimethylaniline is present as the salt in the acid solution, and
`the dimethylammonium group is deactivating and meta-directing, sufficient free dimethyl(cid:173)
`aniline is in equilibrium with the salt to react with nitrous acid, and the equilibrium shifts
`until nitrosation is complete. Nitrous acid does not bring about the nitrosation of benzene
`or even of toluene or mesitylene.
`
`Activation by the dimethylamino group depends on the resonance effect (p. 474), which re(cid:173)
`quires that the dimethylamino group must be able to take up a position coplanar with the benzene
`ring.
`
`If groups larger than hydrogen occupy the ortho positions, coplanarity cannot be attained, and
`activation of the ring is not possible. Thus 2,6, N,N-tetramethylaniline does not undergo reactions
`that require strong activation of the nucleus such as nitrosation and coupling with diazonium salts
`(p. 543).
`
`The diazonium salts from primary amines can be detected readily by reaction with
`aromatic amines or phenols to give highly colored azo compounds (p. 543). Although both
`secondary and tertiary aromatic amines yield nitroso derivatives, the reaction still ca~ be
`used to distinguish between them, because the N-nitroso derivatives are amides of nitrous
`acid. Hence they are not basic and do not dissolve in dilute acids. The p-nitroso derivatives,
`however, form yellow salts with mineral acids. It appears that salt formation does not take
`place with the tertiary amino group, but with the nitroso group, stabilization being brought
`about by resonance with the quinonoid structure (p. 738).
`
`QH,),
`
`QH,),
`
`~
`
`H+
`
`-~
`
`N
`~
`
`.&"'
`
`N"'
`~H
`
`~
`
`¢
`
`+
`N(CH 3)2
`
`N
`bH
`
`Page 10 of 15
`
`
`
`CHAPTER 24. - AROMATIC AMINES AND PHOSPHINES
`
`531
`
`5. Hydrolysis. As in the aliphatic series, an aromatic amino group usually is not dis(cid:173)
`placed readily by hydroxide ion, although in the presence of water at high temperatures
`equilibrium exists between the aromatic amine and the phenol.
`
`This reaction is of little importance in the benzene series but finds commercial application
`in the naphthalene series (pp. 634, 637).
`If, however, a strongly electron-attracting group is present in the para position, the
`amino group can be displaced by a strong base under relatively mild conditions by
`an SNA,2 reaction (p. 496). The reaction is useful for the preparation of pure primary and
`pure secondary aliphatic amines. For primary amines the starting point is the N-alkylaniline,
`which is acetylated and nitrated and then hydrolyzed with sodium hydroxide solution.
`
`RNH
`
`0 + (CH3CO)z0 -~ 0
`
`RNCOCH3
`
`-2_l'bO§_, RNHz + CH3C00Na + o a
`NOz
`Sodium p-nitro(cid:173)
`phenoxide
`
`Secondary amines are obtained from p-nitrosodialkylanilines.
`
`0 + NaOH ---> R 2NH + 0
`
`NR 2
`
`NO
`
`ONa
`
`NO
`
`6. Oxidation. Primary aromatic amines are oxidized to azo compounds by iodoso(cid:173)
`benzene acetate (p. 502) in benzene solution.
`2 ArNH2 + 2 CsH5I(OCOCH3)z ---> ArN=NAr + 2 CsH5I + 4 CH3COOH
`
`Trifluoroperoxyacetic acid (hydrogen peroxide and trijluoroacetic acid) oxidizes the amino group
`to the nitro group. The reaction is particularly useful for the preparation of compounds that
`cannot be obtained by direct substitution, such as p-dinitrobenzene.
`
`OzNQNHz + 3 F3CCOsH ---> OzNQNoz + 3 FsCCOzH + HzO
`
`7. Other Reactions. Aromatic a mines undergo most of the reactions described for
`aliphatic amines. Thus they give condensation products with aldehydes and ketones. Inter(cid:173)
`mediate condensation products frequently are more stable than those of the aliphatic
`amines. For example, the products of reaction of an aldehyde with one or two moles
`of aniline can be isolated.
`CsHsNHz + OCHR ---> CsHsN=CHR + HzO
`2 CsHsNHz + OCHR ---> (CsHsNH)zCHR + HzO
`
`The products from one mole each of amine and aldehyde are known as Schiff bases or anils.
`These intermediates undergo further polymerization and condensation. The condensation
`products have been used as rubber accelerators and antioxidants (p. 782). p-Toluidine
`reacts with formaldehyde in acid solution to give a cyclic condensation product known as
`Troeger's base, which is of stereochemical interest (p. 370).
`
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`CHEMISTRY OF ORGANIC COMPOUNDS
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`Unlike the aliphatic amines, aniline does not react with carbon disulfide at room tem(cid:173)
`perature _to give the dithiocarbamate (p. 34 7). When a solution of aniline and carbon di(cid:173)
`sulfide in alcohol is refluxed, hydrogen sulfide is evolved with the formation of thiocarbanilide.
`CsHsNHCSNHCsHs + H2S
`Thiocarbanilide
`( diphenylthiourea)
`
`Thiocarbanilide at one time was an important rubber accelerator. It now is used chiefly for
`the preparation of 2-mercaptobenzothiazole, which has supplanted it (p. 688).
`When thiocarbanilide is boiled with strong hydrochloric acid, phenyl isothiocyanate
`(phenyl mustard oil), a very pungent compound, is produced.
`CaHsNHCSNHCsHs + HCJ ---" CsH5N=C=S + CaH5NH3+-cJ
`
`Phenyl isothiocyanate reacts readily with primary and secondary amines to give thioureas,
`which are useful for the identification of amines.
`CsH5N=C=S + HzNR --'> CsHsNHCSNHR
`
`Reaction with ammonia gives phenylthiourea, C6H 5NHCSNH2, which is of interest in that it
`is extremely bitter to some persons and tasteless to others. The ability to taste the compound has
`been shown to be hereditary. p-Ethoxyphenylurea ( Dulcin ), p-CzH50C6H 4 NHCONH2, on
`the other hand, is about 100 times sweeter than sucrose. Its toxicity is too great for use
`in foods.
`In the presence of ammonia, aniline reacts with carbon disulfide to give ammonium
`phenyldithiocarbamate.
`CsHsNHz + CSz + NHa ---" CsH5NHCss-+NH4
`
`Removal of hydrogen sulfide from the salt by reaction with lead nitrate (p. 348) gives
`phenyl isothiocyanate.
`
`Primary aromatic amines when heated with chloroform and alkali give the isocyanides or
`carbylamines (p. 260).
`
`Technically Important Aromatic Amines and Their Derivatives
`
`Aniline is by far the most important amine from the technical viewpoint. Over 154 million
`pounds were produced in the United States in 1963, the selling price being about 14 cents per
`pound. Aniline was discovered in 1826 in the products of the destructive distillation of indigo
`(p. 753) and given the name /crystallin because it readily formed crystalline salts. It was detected in
`coal tar in 1834 and called kyanol, because it gave a blue color with bleaching powder. It was redis(cid:173)
`covered in the distillation products of indigo in 1841 and called aniline from afii/, the Spanish word
`for indigo. In the same year it was produced by the reduction of nitrobenzene with ammonium sul(cid:173)
`fide and called benzidam. In 1843 Hofmann (p. 253) proved that all four substances are identical.
`Both the reduction of nitrobenzene and the ammonolysis of chlorobenzene are used in the
`commercial production of aniline. In the reduction process scrap cast-iron turnings and water are
`placed in a cast-iron vessel fitted with a stirrer and a reflux condenser. A small amount of hydro(cid:173)
`chloric acid or ferric chloride is added, and the mixture is heated to remove oxides from the surface
`of the iron, the hydrochloric acid or ferric chloride being converted to ferrous chloride. Nitroben(cid:173)
`zene then is added with vigorous stirring. The iron is converted to black iron oxide, Fe304, which
`is recovered and used as a pigment (p. 517). The aniline is distilled with steam, and the mixed
`vapors are condensed. The aniline layer of the distillate is separated from the water layer and puri(cid:173)
`fied by distillation at reduced pressure. Since aniline is soluble in water to the extent of about 3
`pe.r cent, it must be recovered from the aqueous layer of the distillate. In order to avoid extraction
`with a solvent and recovery of the solvent, the aniline-saturated aqueous layer is returned to the
`steam generator for processing a subsequent batch. In another procedure the aniline is extracted
`from the water with nitrobenzene, and the extract put through the reduction process. Operation of
`a continuous vapor phase hydrogenation process using a fluidized catalyst bed began in 1956.
`
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`533
`
`Since 1926 aniline has been prepared on a large scale by the reaction of chlorobenzene with
`ammonia. The chlorobenzene is heated in a pressure system with 28 per cent aqueous ammonia
`(mole ratio 1 :6) in the presence of cuprous chloride (introduced as cuprous oxide) at 190~210".
`
`A pressure of around 900 p.s.i. develops. The process is continuous, the reactants entering at one end
`of the system and the products leaving the other end. About 5 per cent of phenol and I to 2 per cent
`of diphenylamine are formed as coproducts.
`
`C6HsNH2 + NH,CI
`
`c,rr,cJ + H2o + NH,
`
`C8H,Cl + H,NCsHs + NH,
`
`C.H50H + NH4CI
`Phenol
`c.H,NHC,H, + NH,Cl
`Diphenylamine
`
`These side reactions would take place to a greater extent were it not for the presence of the large
`excess of ammonia. At the end of the reaction the liquid is blown into a column. The free ammonia
`and aniline vaporize and are condensed. Caustic soda is added to the residue to liberate ammonia
`and aniline from their hydrochlorides, convert the phenol into its sodium salt, and precipitate the
`copper salts.
`The first technical use for aniline was in 1856 for the production of mauve, the first commer(cid:173)
`cial synthetic dye (p. 765 ). Aniline still is used almost exclusively as an intermediate in the produc(cid:173)
`tion of other compounds. About 65 per cent of the total production is used in the manufacture of
`rubber accelerators and antioxidants (p. 782), 15 per cent for dyes and dye intermediates, 6 per
`cent for drug manufacture and 2 per cent for photographic developers (p. 566).
`The toluidines, xylidines, phenylenediamines, and most other primary aromatic amines are
`prepared by similar procedures involving reduction of the nitro compounds. m-Nitroaniline is pre(cid:173)
`pared commercially by the partial reduction of m-dinitrobenzene using sodium sulfide as the reduc(cid:173)
`ing agent (p. 517). o- or p-Nitroaniline may be prepared by the ammonolysis of o- or p-nitrochloro(cid:173)
`benzene. This reaction takes place more readily than the ammonolysis of chlorobenzene because of
`the activating effect of nitro groups in the ortho or para position (p. 496).
`Acetanilide was produced to the extent of about 13 million pounds in 1943, but output has
`fallen to about one fourth of this amount since 1948 because of the decrease in the production of
`sulfa drugs (p. 534). A small amount is used as a dye intermediate. Acetanilide was introduced
`as an antipyretic in 1886 under the name antiftbrine, and at one time it was used widely for this
`purpose and as an analgesic. It is highly toxic, however, being similar to aniline in its action, and
`it has been displaced largely by the relativ~ly safer salicylates (p. 600), especially aspirin, which
`was introduced in 1899. Because acetanilide is cheap, it still is used in some proprietary headache
`and pain-killing remedies.
`Lidocaine (Xylocaine), a local anesthetic (p. 162) that now is used widely instead of Novocaine
`(p. 600), is the hydrochloride of 2,6-dimethyl-a-diethylaminoacetanilide and is prepared by the
`following series of reactions.
`
`About 10 million pounds of N,N-dimethylaniline was produced in 1963. It is made from
`aniline and methyl alcohol in the presence of hydrochloric or sulfuric acid in a pressure reactor
`at 220°.
`
`C 0H 5NH2 + 2 CH,OH
`
`It can be made also from aniline and methyl ether over activated alumina at 260°.
`
`Dimethylaniline is used as a dye intermediate (pp. 749, 751, 765) and in the manufacture oftetryl
`(p. 534). Nitrosation of N-methylaniline gives N,4-dinitroso-N-methylaniline (N,4-DNMA), which
`is used in the compounding of rubber (p. 782). N,N'-Di-.9-hutyl-p-phenylenediamine, p-(s(cid:173)
`C4H9NH)2CsH4, is one of the more widely used antioxidants (p. 77) for preventing the polymer(cid:173)
`ization of the unsaturated components of cracked gasoline. Long-chain alkyl derivatives, such as
`N,N'-di-2-octyl·p-phenylenediamine, are used as antioxidants for synthetic rubber.
`Diphenylamine is the principal stabilizer for smokeless powder (p. 427), being added in
`amounts of 1 to 8 per cent of the finished product. Its function is to combine with any oxides of
`nitrogen that are liberated, which otherwise would catalyze further decomposition. Large quantities
`of diphenylamine are used also in the manufacture of phenothiazine (p. 695 ), an intestinal disin-
`
`Page 13 of 15
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`CHEMISTRY OF ORGANIC COMPOUNDS
`
`fectant for animals. When a solution of diphenylamine in concentrated sulfuric acid reacts with
`nitrous or nitric acid or wit!'l their salts or esters, a deep blt,1e color is formed (p. 621 ). The. reaction
`can be used as a test for diphenylamine or for nitrous or nitric acid or their salts or esters.
`Sulfanilic acid and p-toluidine are used principally as dye intermediates. The production of sulfa
`drugs, which amounted to about 6 million pounds in 1945, dropped to 2.5 millio